tbuckley/cabot-search huggingface dataset:
Abstract 5991: Development and characterization of a novel CDK4/6 inhibitor for the treatment of CDK4/6 dependent cancers
Authors: Neil A. O'Brien, Martina S. McDermott, Brendan M. O'Boyle, Justin A. Hilf, Oliver Loson, Kevin Chau, Weiping Jia, Naeimeh Kamranpour, Tong Luo, Raul Ayala, Shawnt Issakhanian, John A. Glaspy, Brian M. Stoltz, Dennis J. Slamon
Journal: Cancer Research (2023)

Abstract CDK4/6 inhibitors give clinical benefit in the treatment of metastatic ER+/HER2- breast cancer (mBC) in combination with endocrine therapy. Although this class of inhibitor has been extensively studied in several other cancer types, CDK4/6 inhibitors have not been approved as a treatment for outside of ER+/HER2- cancer. We evaluated the clinically approved CDK4/6 inhibitors, palbociclib, ribociclib and abemaciclib—in a 500+ cell line screening platform and identified several cancers outside of breast that may have subpopulations that are sensitive to CDK4/6 inhibitors. Kinome and KiNativ analyses helped identify differences in sensitivity/selectivity that we observed between each CDK4/6 inhibitor. Comprehensive molecular profiling of the cell lines at baseline allowed us to screen for potential associations with sensitivity to these compounds. These analyses identified potential biomarkers of sensitivity in non-small cell lung carcinoma (NSCLC) and colorectal cancer (CRC) that will later be evaluated in human clinical studies. Having thoroughly studied the CDK4/6 class and discovered new opportunities for clinical development, we set out to develop a CDK4/6 inhibitor that would have the best properties of the two distinguished class members. Using our proprietary chemistry, we developed UCT-03-008, a potent CDK4/6 small molecular inhibitor with a pharmacology known to enhance therapeutic benefit in mBC. Pharmacokinetic properties of UCT-03-008 are improved over those of other CDK4/6 inhibitors. UCT-03-008 has activity in preclinical models as a monotherapy and yields in vivo efficacy in multiple cancer models outside of ER+/HER2- breast cancer, including CRC and NSCLC. In summary, UCT-03-008 is a CDK4/6 inhibitor with optimized pharmacological properties. Clinical development of this compound will be guided by the biomarker hypotheses developed here. We are currently enrolling patients for treatment with UCT-03-008 in a Phase 1 clinical trial of advanced solid tumors (NCT05103046). Citation Format: Neil A. O'Brien, Martina S. McDermott, Brendan M. O'Boyle, Justin A. Hilf, Oliver Loson, Kevin Chau, Weiping Jia, Naeimeh Kamranpour, Tong Luo, Raul Ayala, Shawnt Issakhanian, John A. Glaspy, Brian M. Stoltz, Dennis J. Slamon. Development and characterization of a novel CDK4/6 inhibitor for the treatment of CDK4/6 dependent cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5991.
Abstract 4439: Negative impact of the GABA pathway on aPD(L)1 immunotherapy
Authors: Svetlana Lyalina, Guadalupe Ortiz-Munoz, Kobe Yuen, Ira Mellman, Sanjeev Mariathasan, Matthew Albert, Deepti Nagarkar, Christine Moussion
Journal: Cancer Research (2023)

Abstract Although gamma-amino butyric acid (GABA) is well characterized as the primary inhibitory neurotransmitter of the central nervous system, its role in the periphery as an immunomodulatory agent is not well understood. Given the widespread use of GABA-A receptor agonists as palliative care in clinical practice, we examined here the impact of GABA on response to immunotherapy in preclinical tumor models and the association of GABA-A receptor agonist usage with outcomes in patients receiving immunotherapy.We show that important genes controlling the GABA pathway are enriched in human tumors versus normal tissue across indications, and tumor cells themselves are able to produce GABA. We found that several key genes of the GABA pathway are upregulated in non-responders to atezolizumab and we derived a 5-gene signature associated with poor outcomes in 2L urothelial cancer patients receiving atezolizumab. Preclinical models further indicated that GABA at the tumor site promotes tumor growth and dampens adaptive immunity preventing response to immunotherapy. Finally, we noted that 45% of urothelial cancer patients received concomitant GABA-A positive allosteric modulators, given as palliative therapy in atezolizumab trials IMvigor-210 and -211. This group exhibited significantly lower OS and PFS as compared to atezolizumab treated patients who did not receive GABA-A positive modulators. A similar negative impact was seen in patients receiving standard of care anti-PD(L)1 immunotherapy in 2L NSCLC using EHR derived deidentified Flatiron Health - Komodo Health claims linked data. These findings highlight the need for further evaluation of concomitant GABA modulators to understand potential risk associated with palliative care in the setting of cancer immunotherapy. © [2022] Komodo Health, Inc All rights reserved Reproduction, distribution, transmission or publication is prohibited Reprinted with permission. Citation Format: Svetlana Lyalina, Guadalupe Ortiz-Munoz, Kobe Yuen, Ira Mellman, Sanjeev Mariathasan, Matthew Albert, Deepti Nagarkar, Christine Moussion. Negative impact of the GABA pathway on aPD(L)1 immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4439.
Abstract 5883: Computational analysis of immune synapses in melanoma tumor microenvironment
Authors: Zichao Liu, Victor G. Wang, Jan Martinek, Ali Foroughi pour, Jie Zhou, Karolina Palucka, Jeffrey H. Chuang
Journal: Cancer Research (2023)

Abstract High-resolution multiplexed tissue imaging such as imaging mass cytometry (IMC) has enabled quantitative cell characterization with preserved tissue architecture. However, the subcellular resolution information has not been fully leveraged yet, as most analyses have focused on cellular or compartment level features. Here, we have developed a robust computational approach integrating cellular spatial and molecular features in multiplexed images to quantify immune synapses. Our approach enables computational detection of subcellular enrichment of T cell co-receptors at immune synapses, which are key regulators of T cell functions in the tumor microenvironment (TME). We quantified immune synapse strength between T cells and various antigen-presenting cells in tumor regions in one melanoma whole tissue immunofluorescence dataset and two independent melanoma IMC datasets covering 99 patients. We observed that sub-localizations of immune synapse-related molecules are highly correlated, e.g. CD3 with CD8. These co-localizations are cell type-specific, with differential behaviors in CD4+ or CD8+ T subtypes. Intra-tumoral T-cell-myeloid synapses are associated with improved T cell proliferation (p = 2.8E-4). In addition, we also observed that cytotoxic T cell - melanoma synapses in immune rich regions are stronger in immune checkpoint inhibition therapy responders than in non-responding patients (p = 0.013). Our approach enables computational resolution of spatial inter-cellular interactions within the TME, is applicable across imaging modalities, and facilities assessment of biological and clinical significance. Citation Format: Zichao Liu, Victor G. Wang, Jan Martinek, Ali Foroughi pour, Jie Zhou, Karolina Palucka, Jeffrey H. Chuang. Computational analysis of immune synapses in melanoma tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5883.
Abstract SY26-01: Mapping cellular plasticity in tumor progression and drug resistance
Authors: Itai Yanai
Journal: Cancer Research (2023)

Abstract Cellular plasticity is emerging as an important driving force underlying cancer progression and drug resistance. In this talk, I will discuss the concept of cancer cell states present in the tumor prior to treatment, as well as those that accompany resistance to increasing drug doses. In particular, I will discuss work published in our recent manuscript 'Cancer cell states recur across tumor types and form specific interactions with the tumor microenvironment' and recent developments in this project. Second, I will discuss our new work of 'Drug-induced adaptation along a resistance continuum in cancer cells'. Citation Format: Itai Yanai. Mapping cellular plasticity in tumor progression and drug resistance. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr SY26-01.
Abstract 3235: Protein kinase C is an upstream regulator of IL13Ra2 and small molecular activator enhances CAR T mediated killing
Authors: Siddharth Subham, John D. Jeppson, Bryan Schatmeyer, Stephen J. Forman, Christine E. Brown, David Akhavan
Journal: Cancer Research (2023)

Abstract Glioblastoma multiforme (GBM) is the most aggressive primary malignant brain cancer with a median survival of 16-20 months. Maximal safe resection and adjuvant chemotherapy improve survival but there is no cure and hence improved therapies are urgently needed. CAR T cell therapy has been FDA approved for hematologic malignancies but there are some barriers to their application for solid tumors in the clinic such as heterogenous tumor antigen expression. Chimeric Antigen Receptor (CAR) T Cells combine the cytolytic potency of T cells with the tumor specificity of an antibody. The interleukin 13 receptor alpha 2 (IL13Rα2) is an important target of CAR T cell therapy in ongoing GBM clinical trials. However, regulation of IL13Ra2 expression in GBM is unclear. Identifying upstream regulators of IL13Rα2 will not only help delineate IL13Rα2 carcinogenesis but also may help improve CAR T cell therapy. Utilizing knockout and overexpression constructs, we have identified protein kinase C family as an upstream regulator of IL13Rα2 transcription and translation in GBM cell lines. We have also identified a small molecule regulator of IL13Rα2, Ingenol-3-Angelate (I3A), that inhibits U87 tumor cell proliferation. Furthermore, I3A enhances IL13Rα2 re-directed CAR T cell mediated tumor cytolysis in vitro. Importantly, I3A treatment increases interferon gamma secretion by T cells. Taken together, our data implicates PKC isoforms as an upstream regulator of IL13Rα2. I3A treatment may serve as a therapeutic strategy to enhance CAR T mediated killing. Citation Format: Siddharth Subham, John D. Jeppson, Bryan Schatmeyer, Stephen J. Forman, Christine E. Brown, David Akhavan. Protein kinase C is an upstream regulator of IL13Ra2 and small molecular activator enhances CAR T mediated killing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3235.
Abstract 4860: PI3K inhibition sensitize cancer cells to tumor treating fields (TTFields)
Authors: Anat Klein-Goldberg, Tali Voloshin, Efrat Zemer-Tov, Rom Paz, Lilach Koren, Kerem Wainer-Katsir, Alexandra Volodin, Bella Koltun, Boris Brant, Yiftah Barsheshet, Tal Kan, Cfir David, Tharwat Haj Khalil, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti
Journal: Cancer Research (2023)

Abstract Introduction: Tumor Treating Fields (TTFields) are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression, ultimately leading to cell death. TTFields therapy is approved for treatment of adult patients with glioblastoma (GBM) or unresectable pleural mesothelioma. Clinical trials are underway in other solid tumors, including ovarian cancer and non-small cell lung carcinoma (NSCLC). The objective of this study is to identify possible mechanisms involved in reduced sensitivity of cancer cell to TTFields, and explore strategies to circumvent them. Methods: Ovarian cancer A2780, GBM U-87 MG, and NSCLC H1299 cells with reduced sensitivity to TTFields were generated by continuous long-term application of TTFields. Luminex multiplex assay was employed to examine changes in signaling pathways in these cells, and specific pathway markers were validated by Western blot. In vivo validation was performed by immunohistochemistry of ovarian cancer, hepatocellular carcinoma, and NSCLC tumor sections from animals treated with TTFields. Next, TTFields concomitant with alpelisib, an isoform specific PI3K inhibitor, was evaluated both in vitro and in an in-vivo model of ovarian cancer. Results: TTFields inflicted a continuous cytotoxic effect on the different cancer cells albeit sensitivity to treatment was reduced following prolonged duration of application. Luminex analysis revealed activation of the PI3K/AKT signaling pathway in treated cells, and kinetics experiments showed that amplitude of AKT signaling increased over time, with significant increases in phosphorylation levels of AKT and focal adhesion kinase (FAK). AKT phosphorylation was also demonstrated in tumor sections of animals treated with TTFields. Experiments performed with concomitant alpelisib sensitized the cells to TTFields and enhanced cytotoxicity in vitro and treatment efficacy in vivo. Conclusions: The current study demonstrates that the PI3K/AKT signaling pathway is involved in reduced cancer cell sensitivity to TTFields, and that PI3K inhibition can further sensitize cancer cells to TTFields. Citation Format: Anat Klein-Goldberg, Tali Voloshin, Efrat Zemer-Tov, Rom Paz, Lilach Koren, Kerem Wainer-Katsir, Alexandra Volodin, Bella Koltun, Boris Brant, Yiftah Barsheshet, Tal Kan, Cfir David, Tharwat Haj Khalil, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti. PI3K inhibition sensitize cancer cells to tumor treating fields (TTFields). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4860.
Abstract 2978: YH013, a novel EGFR x MET bispecific antibody-drug conjugate, exhibits potent antitumor efficacy
Authors: Yanfei Han, Chengzhang Shang, Zhuon li, Zhenyan Han, Jun Li, Zixu Cui, Gao An, Wanjun Hao, Yujie Liu, Hao Li, Baihong Liu, Ellen Zhang, Qingcong Lin, Yi Yang, Yuelei Shen
Journal: Cancer Research (2023)

Abstract Bispecific antibodies (BsAb) that target dual tumor-associated antigens have the advantages of invoking synergistic effects between two signaling pathways, increasing target tissue specificity, and reducing systemic toxicity. By combining the antibody-mediated specific targeting with potent killing from a cytotoxic payload, antibody-drug conjugates (ADC), and especially bispecific ADCs (BsADC), have become powerful therapeutic strategies. EGFR and MET are oncogenic proteins that are co-expressed in a wide range of tumors. Moreover, MET amplification is largely associated with drug resistance of EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC) patients. Biocytogen developed a fully human EGFR x MET BsADC using our proprietary common light chain RenLiteTM mouse platform and knobs-into-holes technology. The BsAb showed enhanced internalization and binding affinity compared to parental monoclonal and monovalent antibodies in the EGFR/MET co-expressing NCI-H1975 cell line. After conjugating the BsAb with monomethyl auristatin E (MMAE) via a protease-cleavable linker, the resulting BsADC, YH013, exhibited a remarkable and dose-dependent anti-tumor efficacy in NCI-H1975 and NCI-H292 cell line-derived xenograft models. Moreover, in multiple patient-derived xenografts of NSCLC and pancreatic ductal adenocarcinoma (PDAC), which co-express EGFR and MET, YH013 demonstrated superior and durable efficacy that outperformed benchmark antibodies at a lower dose (3 mg/kg). Collectively, these results suggest that YH013 can be an effective treatment option for EGFR and MET co-expressing tumors and overcome MET-driven EGFR-TKI resistance to improve patient outcomes. Citation Format: Yanfei Han, Chengzhang Shang, Zhuon li, Zhenyan Han, Jun Li, Zixu Cui, Gao An, Wanjun Hao, Yujie Liu, Hao Li, Baihong Liu, Ellen Zhang, Qingcong Lin, Yi Yang, Yuelei Shen. YH013, a novel EGFR x MET bispecific antibody-drug conjugate, exhibits potent antitumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2978.
Abstract 4305: Germline structural variants shape prostate cancer clinical and molecular evolution
Authors: Nicholas K. Wang, Alexandre Rouette, Kathleen E. Houlahan, Takafumi N. Yamaguchi, Julie Livingstone, Chol-Hee Jung, Peter Georgeson, Michael Fraser, Yu-Jia Shiah, Cindy Q. Yao, Vincent Huang, Natalie S. Fox, Natalie Kurganovs, Katayoon Kasaian, Veronica Y. Sabelnykova, Jay Jayalath, Kenneth Weke, Helen Zhu, Theodorus van der Kwast, Tony Papenfuss, Housheng H. He, Niall M. Corcoran, Robert G. Bristow, Alexandre R. Zlotta, Christopher Hovens, Paul C. Boutros
Journal: Cancer Research (2023)

Abstract Inherited genetic variation profoundly influences cancer risk and outcome. While the impact of germline single nucleotide polymorphisms has been well-studied in several cancer types, the effects of germline structural variants (gSVs) on cancer biology and clinical outcomes is largely unknown. From our cohort of 300 men with localized, intermediate risk prostate cancer, we identified 6,003 gSVs present in at least 3% of patients; 48 were associated with recurrent somatic alterations or clinical outcome. Of these, approximately 50% were associated with expression of nearby genes or intersected with exons or regulatory regions. Using external cohorts, we validated three gSVs that were strongly associated with poor clinical outcomes, including an inversion at chr14q24.1 present in ~20% of patients. Notably, a strong synergistic effect on outcome was observed in patients with somatic TP53 alterations or high genomic instability, defining a new aggressive prostate cancer subtype with chr14INV as a novel, recurrent biomarker. Citation Format: Nicholas K. Wang, Alexandre Rouette, Kathleen E. Houlahan, Takafumi N. Yamaguchi, Julie Livingstone, Chol-Hee Jung, Peter Georgeson, Michael Fraser, Yu-Jia Shiah, Cindy Q. Yao, Vincent Huang, Natalie S. Fox, Natalie Kurganovs, Katayoon Kasaian, Veronica Y. Sabelnykova, Jay Jayalath, Kenneth Weke, Helen Zhu, Theodorus van der Kwast, Tony Papenfuss, Housheng H. He, Niall M. Corcoran, Robert G. Bristow, Alexandre R. Zlotta, Christopher Hovens, Paul C. Boutros. Germline structural variants shape prostate cancer clinical and molecular evolution. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4305.
Abstract 2424: Development of radiation sensitivity evaluation platform in esophageal cancer patient derived organoids
Authors: Jung Eun Kim, Mi-Hyeon Jeong, Thunyaporn Ravangnam, Sunghun Ju, Dong Woo Lee, Bosung Ku, Dongryul Oh
Journal: Cancer Research (2023)

Abstract Radiation therapy (Radiotherapy) is a highly effective treatment with wide range of cancer curing. Radiotherapy allows the cancer cells to be killed or reduced in number while protecting the majority of other organs and tissues in the body. Radiotherapy is commonly used with chemotherapy or immunotherapy or radiosensitizer drugs for enhancing the treatment efficacy. Predicting individual radiation sensitivity is very important in determining the direction of future treatment after cancer diagnosis. However, it is lack of accurate and relevant preclinical model for evaluation of radiation sensitivity.In this study, we developed the platform for radiosensitivity evaluation using the Esophageal cancer patient derived organoids. Biopsy tissues from Esophageal cancer were digested to single cells and then dispensed with ECM on pillar plate (MBD co.) to forming organoids. After organoid formation, the organoids were exposed to radiation with increasing dosage. Cell viability and radiation sensitivity were calculated by 3D Celltiter glo method and Calcein AM staining. Radiation sensitivity index was determined based on radiation response and organoid growth.We included 22 patients with ESCC treat with radiation therapy from Samsung Medical Center. After surgery, we compared radiation sensitivity index with pathological grade for sensitivity and specificity of radio sensitivity evaluation platform. The sensitivity was 75.00% (95% CI 34.91% - 86.81%) and the specificity was 71.43% (95% CI 41.90% - 91.61%). This resulted in an accuracy in this population of 72.73% (95% CI 49.78% - 89.27%).This study has a very high correlation to patient matched clinical outcomes of radiation sensitive group or non-sensitive group. This radiation sensitivity evaluation platform could contribute to precision medicine in Esophageal cancer patients and it can be helpful to make decision how to cure of cancer. Citation Format: Jung Eun Kim, Mi-Hyeon Jeong, Thunyaporn Ravangnam, Sunghun Ju, Dong Woo Lee, Bosung Ku, Dongryul Oh. Development of radiation sensitivity evaluation platform in esophageal cancer patient derived organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2424.
Abstract 3144: Mapping the functional interactions at the tumor-immune checkpoint interface
Authors: Behnaz Bozorgui, Elisabeth K. Kong, Augustin Luna, Anil Korkut
Journal: Cancer Research (2023)

Abstract The interactions between tumor intrinsic processes and immune checkpoints can mediate the immune evasion by tumors and responses to immunotherapy. It is, however, challenging to identify functional interactions due to the prohibitively complex molecular landscape of the tumor-immune interfaces. We address this challenge with a statistical analysis framework, termed immuno-oncology gene interaction maps (ImogiMap). ImogiMap quantifies tumor-immune checkpoint interactions based on their co-associations with immune-associated phenotypes. The interactions are statistically validated for significance, robustness, and specificity. The outcome is a catalog of maps that quantify the interactions at the tumor-immune interface for diverse immune phenotypes and checkpoints. We demonstrate that applications of ImogiMap on immune checkpoints and T-cell dysfunction signatures genes recapitulates the previously reported interaction of SERPINB9 and immune checkpoints in the tumor microenvironment. Our analyses also suggest other immune checkpoint and T-cell dysfunction signatures interactions that are significantly associated with IFNγ expression in uterine corpus endometrial carcinoma and basal-like breast cancer. We also provide open-source software and a user-friendly web application to enable future applications and rapid adoption of ImogiMap. Such applications may guide the discovery of previously unknown tumor-immune interactions and help the identification of immunotherapy targets. Citation Format: Behnaz Bozorgui, Elisabeth K. Kong, Augustin Luna, Anil Korkut. Mapping the functional interactions at the tumor-immune checkpoint interface [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3144.